Vol.:(0123456789)

Clinical Pharmacokinetics (2020) 59:1195–1216 https://doi.org/10.1007/s40262-020-00924-9

REVIEW ARTICLE

Pharmacokinetics/Pharmacodynamics of Antiviral Agents Used to Treat SARS‑CoV‑2 and Their Potential Interaction with Drugs and Other Supportive Measures: A Comprehensive Review by the PK/PD of Anti‑Infectives Study Group of the European Society of Antimicrobial Agents

Markus Zeitlinger1  · Birgit C. P. Koch2 · Roger Bruggemann3 · Pieter De Cock4 · Timothy Felton5,6 · Maya Hites7 · Jennifer Le8 · Sonia Luque9,10 · Alasdair P. MacGowan11 · Deborah J. E. Marriott12,13 · Anouk E. Muller14 · Kristina Nadrah15,16 · David L. Paterson17,18 · Joseph F. Standing19,20 · João P. Telles21 · Michael Wölfl‑Duchek22 · Michael Thy23,24 · Jason A. Roberts25,26,27,28,29 · the PK/PD of Anti‑Infectives Study Group (EPASG) of the European Society of Clinical Microbiology, Infectious Diseases (ESCMID)

Published online: 28 July 2020 © The Author(s) 2020

AbstractThere is an urgent need to identify optimal antiviral therapies for COVID-19 caused by SARS-CoV-2. We have conducted a rapid and comprehensive review of relevant pharmacological evidence, focusing on (1) the pharmacokinetics (PK) of potential antiviral therapies; (2) coronavirus-specific pharmacodynamics (PD); (3) PK and PD interactions between proposed combina-tion therapies; (4) pharmacology of major supportive therapies; and (5) anticipated drug–drug interactions (DDIs). We found promising in vitro evidence for remdesivir, (hydroxy)chloroquine and favipiravir against SARS-CoV-2; potential clinical benefit in SARS-CoV-2 with remdesivir, the combination of lopinavir/ritonavir (LPV/r) plus ribavirin; and strong evidence for LPV/r plus ribavirin against Middle East Respiratory Syndrome (MERS) for post-exposure prophylaxis in healthcare workers. Despite these emerging data, robust controlled clinical trials assessing patient-centred outcomes remain imperative and clinical data have already reduced expectations with regard to some drugs. Any therapy should be used with caution in the light of potential drug interactions and the uncertainty of optimal doses for treating mild versus serious infections.

On behalf of the PK/PD of Anti-Infectives Study Group (EPASG) of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID); all authors are affiliated with this group.

Electronic supplementary material The online version of this article (https ://doi.org/10.1007/s4026 2-020-00924 -9) contains supplementary material, which is available to authorized users.

* Markus Zeitlinger markus.zeitlinger@meduniwien.ac.at

* Jason A. Roberts j.roberts2@uq.edu.au

Extended author information available on the last page of the article

Key Points

The European Society of Clinical Microbiology and Infectious Diseases (ESCMID) PK/PD Study Group has especially convened a group of clinical and PK/PD experts to provide guidance for all relevant drug therapies for infections caused by the SARS-COV-2 virus. The underlying presents guidance at a high level of detail on the key pharmacokinetic/pharmacodynamic characteristics of drugs at the current most commonly used antiviral regimens, clinically significant drug–drug interactions, and the effect of extracorporeal therapies (e.g. renal replacement therapy, extracorporeal mem-brane oxygenation) on dosing requirements.

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1196 M. Zeitlinger et al.

1 Drugs Active Against SARS‑CoV‑2

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was declared a global pandemic on 11 March 2020 and has triggered enormous, unrelenting and ever-increasing demands on health systems in countries globally. The number of patients infected with this novel coronavirus escalated dramatically, with the first clinical trial for a vac-cine initiated in the US on 16 March 2020. There has been an unprecedented and immediate need to define and opti-mize treatment for infected patients. However, the evidence for therapies against SARS-CoV-2 is inadequate, leading many medical teams to prescribe drugs based on mechanis-tic data with limited clinical data supporting their activity. This lack of knowledge is also manifest in highly variable doses or proposed duration of therapy for treatment. It is also noteworthy that many drugs are not uniformly available throughout the world; a therapeutic option for COVID-19 in one country may not be available in another. Inevitably, this heterogeneity of practice and accessibility may lead to patients receiving suboptimal therapy because of a lack of appropriate and readily available data for drugs that are obtainable in a particular country.

Coronaviruses commonly cause infection in non-human animal hosts, and therefore animal models might be informa-tive to investigate drugs that may be applicable for use in humans. Along with preclinical data from animal models, there are emerging reports from in vitro cell culture models that provide information on the mechanism of action and antiviral effects of tested compounds [1]. Application of in silico modeling and simulation techniques can then advance infection model-defined exposure targets to identify doses appropriate for human use. While this process provides highly valuable direction for antiviral therapeutic selection when there is an emergent need for such drugs, these meth-ods are analogous to those applied in the drug development process. The clinical utility of preclinically validated dos-ing regimens relies heavily on the available pharmacokinetic (PK) data used in the simulation process for the particular drug. That is, PK data obtained from healthy volunteers rather than the population of interest (i.e. severely ill patients with acute respiratory distress syndrome [ARDS]) may not be applicable due to differences in bioavailability for orally or subcutaneously administered drugs, and alterations in the drug’s volume of distribution (Vd) and clearance (CL) that may result in sub- or supratherapeutic exposure; therefore careful interpretation for clinical use is essential [2]

Therapeutic agents available for COVID-19 can intro-duce other treatment challenges, particularly drug interac-tions. Various compounds that have been proposed for the treatment of SARS-CoV-2 are affected by the cytochrome P450 (CYP)-metabolizing system as either substrates,

enzyme inhibitors or enzyme inducers, and consideration of these interactions on dosing requirements of concomitant SARS-CoV-2 or other supportive drug therapies is essen-tial. For instance, lopinavir/ritonavir (LPV/r) combination has strong inhibitory effects on CYP3A4 and CYP2D6, which also metabolize hydroxychloroquine (another prob-able agent active against SARS-CoV-2), which may result in an increase in potential toxic effects such as Torsades de pointes [3].

With the significant uncertainty regarding the choice and dose of drug therapy for patients with active COVID-19 disease, there is a clear need for a review of potential treatments and interpretation of dosing considerations to optimize treatment based on current evidence. The aim of this narrative review is to summarize available literature to guide treatment choices in clinical trials, and to inform local and national policymakers to enable clinicians to optimize the treatment regimens for patients outside trials with SARS-CoV-2 infection.

2 Search Methodology

Literature regarding the treatment of SARS-CoV-2 is highly dynamic and evolving. Many results have not yet been published in their final form. In order to allow for a fast evaluation of the most relevant treatment practices at hos-pitals worldwide, the PK/PD of Anti-Infective Study Group (EPASG) of the European Society of Clinical Microbiol-ogy and Infectious Diseases (ESCMID) established rapid communication by social media channels. In addition, the World Health Organization website was evaluated for reports pertinent to our review, including preprints [4]

Once the drugs of interest were identified (Table 1) their PK/pharmacodynamic (PK/PD) characteristics were sum-marized (Table 2). Subsequently, we searched databases to identify single and combination therapies being evalu-ated in clinical trials. Searches of the PubMed and Embase databases (no date limits) were then performed using the search strategy ‘(drug name) AND (coronavirus)’ to identify clinical trials, retrospective clinical studies, and animal or in vitro studies on the drug therapies (Table 3). In addition, information on drug–drug interactions (DDIs) was extracted [5]. Teams of at least three authors extracted and agreed upon data presented in each table. We deliberately excluded analysis of combinations with remdesivir since the currently open trials investigate only monotherapy.

Because COVID-19 requires intensive care treatment in up to 10% of infected patients, electronic supplemen-tary Table 1 presents the most commonly used supportive drugs, while electronic supplementary Table 2 presents the potential interactions of these drugs with antivirals. Unless specifically stated, the Summary of Product characteristics

1197Drugs, PK/PD and DDI for SARS-CoV-2 Therapy

(SmPC) or package leaflets of medications have been used as the basis for the assessment of DDIs. These interactions are also constantly updated on online platforms, such as the COVID-19 drug interaction webpage maintained by the University of Liverpool [3]. Extracorporeal support treat-ments might also be necessary for critically ill patients with COVID-19 and, as such, in Table 4 we describe the influence of extracorporeal support treatments on antiviral PK.

3 List of experimental antiviral agents explored for treatment of Covid 19

3.1 Antiviral Agents for the Treatment of COVID‑19

Table 1 contains general information about the key drugs currently suggested for the treatment of COVID-19. Most agents were originally approved for the treatment of other viral infections. The exception is (hydroxy)chloroquine, an immunomodulatory drug with known antiviral activity that has been used for over 60 years, primarily to treat malaria and, more recently, autoimmune diseases, such as systemic lupus erythematosus and inflammatory arthritis. Some of the agents listed have been studied with related viruses, such as Middle East Respiratory Syndrome (MERS) coronavirus. Most agents discussed in this article purportedly have direct mechanisms of action against SARS-CoV-2. As COVID-19 disease has emerged only recently, drugs currently being used are in various phases of clinical trials and none are approved for use in COVID-19, except for the very recent approval of remdesivir. The dosing regimens are based on current knowledge, derived from other indications, and may change in the future when new data become available. Dos-ing regimens in children are unavailable for most agents. In general, the heterogeneous total daily doses for drugs against COVID-19 disease are similar to, or greater than, that used for other indications.

3.2 Pharmacokinetics/Pharmacodynamics (PK/PD) of Antiviral Agents for the Treatment of COVID‑19

Table 2 summarizes the data on the PK/PD properties of the agents recommended for SARS-CoV-2 and other viruses. The available data are limited and are based primarily on in vitro studies in various cell lines. Drug potency is usu-ally presented as the half maximal effective concentration (EC50), which varies between viruses. The EC50 values for other viruses are compared against SARS-CoV-2, with a lower EC50 indicating increased potency. While EC90 is usu-ally preferred as a therapeutic target for antivirals, it can only be inferred from EC50 when the Hill coefficient is 1 (in which case EC90 is ninefold higher than EC50). Since the

Hill coefficient is not routinely reported, we used EC50 to compare the relative potencies of the antivirals reviewed.

Data on other coronaviruses have been summarized; how-ever, where data are unavailable for coronaviruses, other pathogens are reported. For chloroquine and PegIFN-α2β, measured intracellular concentrations are correlated with the in vitro EC50 and, as such, serve as the PK/PD index [6, 7]; however, there are no studies comparing various PK/PD indices for these agents.

The EC50 values for remdesivir, chloroquine, and riba-virin against SARS-CoV-2 were compared with those of MERS. For both remdesivir and ribavirin, the EC50 values were higher than for MERS, indicating that a larger dose may be needed to treat COVID-19. The EC50 value of chlo-roquine was within the same range for SARS-CoV-2 and MERS. In an in vitro study, Yao et al. compared chloroquine with hydroxychloroquine and reported that hydroxychloro-quine was more potent than chloroquine [7], although cau-tion interpreting these results is warranted since different EC50 values were reported depending on whether experi-ments were conducted for 24 or 48 h. Since EC50 is not a time-dependent parameter, this calls into question how reliable the estimate is and how well it may translate to an in vivo target. In addition, this study has recently undergone a critical review by authors from the US FDA [8]. Further-more, other studies have conversely found chloroquine to be more potent than hydroxychloroquine [9], and emerg-ing data from randomized controlled trials (RCTs) [10] and large observational studies [11] suggest that both chloro-quine and hydroxychloroquine result in increased mortal-ity when used in COVID-19. While we include chloroquine and hydroxychloroquine in the summary of evidence, there is great uncertainty as to the clinical role of these drugs in hospitalized COVID-19 patients. Indeed, meanwhile, several negative studies have led to discontinuation of the use of these two drugs in many clinical studies in many countries [12, 13], yet other countries still continue to use these widely available drugs due to a lack of alternatives.

Several interferons (IFNs), including IFN-α, PegIFN-α2β, IFN-α1β and IFN-β1β, have been examined for the treatment of COVID-19; however, they are administered as adjuvant therapy with other anti-COVID-19 drugs.

The currently available data on drug efficacy and PK/PD targets for COVID-19 are inadequate to support therapeu-tic drug monitoring; however, some data on plasma con-centrations are available in the literature (Table 2). When drug concentrations are available in the literature, it may be prudent to evaluate individual concentrations in patients in which high variability in PK combined with an increased likelihood of DDIs and adverse effects can be expected, i.e. typically critically ill patients.

A shortcoming of the data presented in Table 2 is the fact that the total concentrations of the drug were reported by

1198 M. Zeitlinger et al.

Tabl

e 1

Ant

ivira

ls a

nd su

ppor

tive

drug

s use

d to

trea

t CO

VID

-19

Subs

tanc

e ge

neric

na

me

Nor

mal

ap

prov

ed

indi

catio

n

Stud

ied

viru

sSt

udy

phas

e fo

r CO

VID

-19

Ant

ivira

l m

ode

of

actio

n

Supp

lier/

maj

or c

oun-

tries

whe

re

avai

labl

e

Cur

rent

ly

used

dos

e fo

r app

rove

d in

dica

tion

(mg)

Adu

lt do

sing

in C

OV

ID-1

9 (m

g)C

hild

dos

ing

in

COV

ID-1

9 (m

g)Ro

ute

of

adm

inis

-tra

t-ion

Rout

e of

el

imin

atio

n

Rem

desi

-vi

rA

ntiv

iral

unde

r in

vesti

-ga

tion;

FD

A

emer

-ge

ncy

use

auth

ori-

zatio

n to

CO

VID

-19

COV

ID-

19,

MER

S-C

oV,

SAR

S-C

oV,

HC

oV-

229E

, H

CoV

-O

C43

Phas

e II

I/IV

(N

CT0

4292

899;

N

CT0

4292

730;

N

CT0

4280

705;

N

CT0

4321

616;

N

CT0

4315

948)

Vira

l RN

A

poly

-m

eras

e in

hibi

tor

Gile

ad®

Euro

peU

SA

200 

mg

on d

ay

1, fo

llow

ed

by 1

00 m

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y (to

tal

10–1

4 da

ys)

200 

mg

on d

ay 1

follo

wed

by

100 

mg/

day

on d

ays 2

–10

WT

< 40

 kg:

5 m

g/kg

lo

ad, t

hen

2.5 

mg/

kg/2

4 h

WT

≥ 40

 kg:

20

0 m

g lo

ad, t

hen

100 

mg/

24 h

[39]

IVN

A

Chl

oro-

quin

eA

ppro

ved

antim

a-la

rial;

FDA

em

er-

genc

y us

e au

thor

i-za

tion

to

COV

ID-

19

COV

ID-

19,

SAR

S-C

oV,

HC

oV-

OC

43

Cel

l cul

ture

s/co

-cu

lture

sPh

ase

III/I

V

(NC

T043

6233

2;

NC

T043

3160

0;

NC

T043

5119

1)

Inhi

bitio

n of

end

o-so

me-

med

iate

d vi

ral

entry

, an

d pH

-de

pend

-en

t ste

ps

in v

iral

repl

ica-

tion

[40]

Sano

fi-A

vent

is®

Glo

bal

100 

mg/

24 h

600 

mg/

12 h

on

day

1, fo

llow

ed

by 3

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g bi

d on

day

s 2–5

; al

tern

ativ

e: 5

00 m

g/12

 h o

ver

5 da

ys [7

]

NA

PO o

r IV

50%

rena

l cl

eara

nce

(exc

rete

d un

chan

ged

in th

e ur

ine)

; m

etab

o-liz

ed b

y C

YP2

C8,

C

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A4

and,

to

less

er

exte

nt,

CY

P2D

6Lo

pina

vir/

riton

avir

App

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d an

tivira

lCO

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ERS-

CoV

Phas

e IV

HIV

pr

otea

se

inhi

bito

r/bo

ost

of o

ther

pr

otea

se

inhi

bi-

tors

Abb

ott®

Glo

bal

400 

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12 h

+

100 

mg/

12 h

LPV

/r 40

0/10

0 m

g/12

 h P

O,

14 d

ays [

37]

(a) A

ge 1

4 da

ys–

12 m

onth

s:

16 m

g/4 

mg

(LPV

/r)/

kg/1

2 h

(b) A

ge

12 m

onth

s–18

 yea

rs:

(i) W

T <

15 k

g:

13 m

g/3.

25 m

g (L

PV/r)

/kg/

12 h

; (ii)

W

T ≥

15 to

40 

kg:

11 m

g/2.

75 m

g (L

PV/r)

/kg/

12 h

[41]

POLP

V: m

etab

-ol

ized

by

CY

P3A

Rito

navi

r: C

YP3

A4

and,

to

a le

sser

ex

tent

, C

YP2

D6

[42]

1199Drugs, PK/PD and DDI for SARS-CoV-2 Therapy

Tabl

e 1

(con

tinue

d)

Subs

tanc

e ge

neric

na

me

Nor

mal

ap

prov

ed

indi

catio

n

Stud

ied

viru

sSt

udy

phas

e fo

r CO

VID

-19

Ant

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l m

ode

of

actio

n

Supp

lier/

maj

or c

oun-

tries

whe

re

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labl

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Cur

rent

ly

used

dos

e fo

r app

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d in

dica

tion

(mg)

Adu

lt do

sing

in C

OV

ID-1

9 (m

g)C

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dos

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in

COV

ID-1

9 (m

g)Ro

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of

adm

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t-ion

Rout

e of

el

imin

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n

Favi

pira

vir

App

rove

d an

tivira

lCO

VID

-19

Phas

e II

I (N

CT0

4349

241;

N

CT0

4356

495;

N

CT0

4303

299;

N

CT0

4373

733;

N

CT0

4351

295;

N

CT0

4361

461;

N

CT0

4345

419)

Vira

l RN

A

poly

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eras

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hibi

tor

Fujifi

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ma

Che

mic

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1600

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12 h

on

day

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600 

mg/

12 h

on

day

s 2–5

Und

er st

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NA

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unde

r de

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[43]

Gen

etic

va

riant

in

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tra

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gp;

AB

CB

1)

and

met

ab-

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n in

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bot

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3]R

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tivira

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Cel

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7668

8)

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: m

ultip

le

poss

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m

echa

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sms

Gen

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pe40

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500 

mg/

12 h

or 5

00 m

g/8 

h IV

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4]N

AA

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l cl

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(30%

), so

me

feca

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Arb

idol

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mife

no-

vir

App

rove

d an

tivira

lCO

VID

-19

Phas

e IV

(N

CT0

4350

684;

N

CT0

4260

594;

N

CT0

4286

503)

Inhi

bits

m

em-

bran

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sion

, sti

mu-

latio

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the

imm

une

syste

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ian

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arch

C

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arm

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Insti

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Chi

na

50–2

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g/6 

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0 m

g/8 

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4]Sa

fety

unc

lear

[45]

POV

ia th

e fe

ces,

met

abo-

lized

in

hepa

tic

and

inte

sti-

nal m

icro

-so

mes

(33

met

abo-

lites

kn

own)

, C

YP3

A4

[46]

1200 M. Zeitlinger et al.

Tabl

e 1

(con

tinue

d)

Subs

tanc

e ge

neric

na

me

Nor

mal

ap

prov

ed

indi

catio

n

Stud

ied

viru

sSt

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phas

e fo

r CO

VID

-19

Ant

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ode

of

actio

n

Supp

lier/

maj

or c

oun-

tries

whe

re

avai

labl

e

Cur

rent

ly

used

dos

e fo

r app

rove

d in

dica

tion

(mg)

Adu

lt do

sing

in C

OV

ID-1

9 (m

g)C

hild

dos

ing

in

COV

ID-1

9 (m

g)Ro

ute

of

adm

inis

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t-ion

Rout

e of

el

imin

atio

n

Hyd

roxy

-ch

loro

-qu

ine

App

rove

d an

tima-

laria

l; FD

A

emer

-ge

ncy

use

auth

ori-

zatio

n to

CO

VID

-19

COV

ID-1

9Ph

ase

III/I

V

(NC

T042

6151

7;

NC

T043

6233

2;

NC

T043

3496

7;

NC

T043

5961

5;

NC

T043

1637

7)

Inhi

bitio

n of

end

o-so

me-

med

iate

d vi

ral

entry

, an

d pH

-de

pend

-en

t ste

ps

in v

iral

repl

ica-

tion

[40]

Sano

fi-A

vent

is®

Euro

pe

100 

mg/

24 h

400 

mg/

day

for 5

 day

s (N

CT0

4261

517)

PO

40

0 m

g/12

 h o

n da

y 1

follo

wed

by

200

 mg/

12 h

on

days

2–5

[7]

NA

PO50

% re

nal

clea

ranc

e (e

xcre

ted

unch

ange

d in

the

urin

e);

met

abo-

lized

by

CY

P2C

8,

CY

P3A

4,

and,

to

less

er

exte

nt,

CY

P2D

6Pe

gIFN

-α2

βA

ppro

ved

antiv

iral

COV

ID-

19,

MER

S-C

oV,

HC

oV

Phas

e IV

(N

CT0

4254

874;

NC

T042

9172

9)

Adj

uvan

t tre

at-

men

t: en

hanc

e-m

ent o

f ph

ago-

cytic

/cy

toto

xic

mec

ha-

nism

s

– Euro

pe1.

5 μg

/kg/

wee

k SC

45–5

0 μg

/12 

h (N

CT0

4254

874;

NC

T042

9172

9)N

AN

ebul

ized

; SC

Rena

l cle

ar-

ance

[47]

IFN

-α1β

App

rove

d an

tivira

lCO

VID

-19

, M

ERS-

CoV

, H

CoV

Early

pha

se I

(NC

T042

9388

7)A

djuv

ant

treat

-m

ent:

enha

nce-

men

t of

phag

o-cy

tic/

cyto

toxi

c m

echa

-ni

sms

– Chi

na–

10 μ

g/12

 h (N

CT0

4293

887)

NA

Neb

uliz

edRe

nal c

lear

-an

ce [4

7]

1201Drugs, PK/PD and DDI for SARS-CoV-2 Therapy

Tabl

e 1

(con

tinue

d)

Subs

tanc

e ge

neric

na

me

Nor

mal

ap

prov

ed

indi

catio

n

Stud

ied

viru

sSt

udy

phas

e fo

r CO

VID

-19

Ant

ivira

l m

ode

of

actio

n

Supp

lier/

maj

or c

oun-

tries

whe

re

avai

labl

e

Cur

rent

ly

used

dos

e fo

r app

rove

d in

dica

tion

(mg)

Adu

lt do

sing

in C

OV

ID-1

9 (m

g)C

hild

dos

ing

in

COV

ID-1

9 (m

g)Ro

ute

of

adm

inis

-tra

t-ion

Rout

e of

el

imin

atio

n

IFN

-αA

ppro

ved

antiv

iral

COV

ID-

19,

MER

S-C

oV,

HC

oV

Not

app

licab

le

(NC

T042

5187

1)

[48]

Adj

uvan

t tre

at-

men

t: en

hanc

e-m

ent o

f ph

ago-

cytic

/cy

toto

xic

mec

ha-

nism

s

– Chi

na–

5 m

illio

n IU

/12 

h (N

CT0

4251

871)

[4

8]IF

N-α

200

,000

– 40

0,00

0 IU

/kg

or

2–4 

μg/k

g in

2 m

L ste

rile

wat

er, n

ebul

i-za

tion

two

times

per

da

y fo

r 5–7

 day

s [45

]

Neb

uliz

edRe

nal c

lear

-an

ce [4

7]

IFN

-β1β

App

rove

d an

tivira

lCO

VID

-19

, M

ERS-

CoV

, H

CoV

Phas

e II

(N

CT0

4276

688)

Adj

uvan

t tre

at-

men

t: en

hanc

e-m

ent o

f ph

ago-

cytic

/cy

toto

xic

mec

ha-

nism

s

– Euro

pe,

Chi

na

25 μ

g SC

in

ject

ion

alte

rnat

e da

y

25 μ

g SC

inje

ctio

n al

tern

ate

day

for 3

 day

s (N

CT0

4276

688)

SCRe

nal c

lear

-an

ce [4

7]

Cam

osta

tA

ppro

ved

for

chro

nic

panc

rea-

titis

COV

ID-

19,

MER

S-C

oV,

SAR

S-C

oV

Phas

e I/I

I/III

(N

CT0

4353

284;

N

CT0

4321

096;

N

CT0

4374

019;

N

CT0

4355

052)

Blo

cks

inte

rac-

tion

betw

een

the

S1

prot

ein

and

the

SAR

S-C

oV-2

ta

rget

ce

ll

Nic

hi Ik

oJa

pan

200 

mg/

8 h

200 

mg/

12 h

or 8

 hN

APO

Rena

l cl

eare

nce

[49]

1202 M. Zeitlinger et al.

the majority of papers, or information as to whether total or free concentrations were reported is not available at all. This must be taken into account when PK/PD calculations are performed, since, unusually, only the free fraction will be active.

3.3 Combination SARS‑CoV‑2 Antiviral Agents and Associated Drug–Drug Interactions

As there are no approved COVID-19 therapies, combina-tion therapy against SARS-CoV-2 with agents exhibiting different modes of action may have a role in helping to opti-mize therapy until clinical trial data become available. This combination approach is consistent with the management of many viral, fungal, and bacterial infections where there are suboptimal single-agent treatment options. We aimed to assess the evidence of repurposed antiviral combinations that were not specifically designed to treat SARS-CoV-2.

The strongest RCT evidence exists for remdesivir, which has been shown to reduce the recovery time for moder-ate–severe COVID-19 in comparison with standard care (11 vs. 15 days [14]; p < 0.001). These data have now led some to declare remdesivir to be the standard of care for COVID-19 disease, even though there was no significant difference in mortality between the remdesivir and standard care groups.

Other, albeit less-compelling, data exist for LPV/r plus ribavirin therapy (retrospective, case–control study) result-ing in a reduction in mortality, acute respiratory distress syndrome  (ARDS), and viral shedding in the treatment of SARS (Table 3). However, extrapolating these data to SARS-CoV-2 should be undertaken with caution as LPV/r and another HIV protease inhibitor, nelfinavir, exhibit good activity against SARS [15, 16] but are less effective against MERS [17]. Another potential combination includes LPV/r, ribavirin and IFN (prospective, non-randomized, compara-tive controlled study), resulting in shorter duration of viral shedding and hospital stay when compared with LPV/r alone. Randomized trials involving these drugs, based on their promising in vitro activity, will provide important guidance. Of note, we warn against the use of hydroxychlo-roquine in combination with other drugs that may prolong the QT interval due to potentially life-threatening adverse effects [11]. In a large cohort study, all patients who received hydroxychloroquine for the treatment of pneumonia associ-ated with COVID-19 were at high risk of QTc prolongation, but concurrent treatment with azithromycin was associated with greater changes in QTc [18]. However, since combina-tions of QTc-prolonging drugs do not necessarily result in additive QTc prolongation, a case-by-case evaluation seems warranted [19].

Tabl

e 1

(con

tinue

d)

Subs

tanc

e ge

neric

na

me

Nor

mal

ap

prov

ed

indi

catio

n

Stud

ied

viru

sSt

udy

phas

e fo

r CO

VID

-19

Ant

ivira

l m

ode

of

actio

n

Supp

lier/

maj

or c

oun-

tries

whe

re

avai

labl

e

Cur

rent

ly

used

dos

e fo

r app

rove

d in

dica

tion

(mg)

Adu

lt do

sing

in C

OV

ID-1

9 (m

g)C

hild

dos

ing

in

COV

ID-1

9 (m

g)Ro

ute

of

adm

inis

-tra

t-ion

Rout

e of

el

imin

atio

n

Naf

amo-

stat

App

rove

d fo

r pan

-cr

eatit

is

COV

ID-

19,

MER

S-C

oV,

SAR

S-C

oV

Phas

e II

(N

CT0

4352

400)

Blo

cks t

he

inte

rac-

tion

betw

een

the

S1

prot

ein

and

the

SAR

S-C

oV-2

ta

rget

ce

ll

Nic

hi Ik

oJa

pan

20–5

0 m

g IV

(p

roph

ylax

is

of p

ancr

eati-

tis) [

50]

NA

NA

IVRe

nal

clea

renc

e [5

1]

Unc

lear

: Mul

tiple

pos

sibl

e m

echa

nism

sC

OVI

D-1

9 C

oron

aviru

s dis

ease

201

9, M

ERS-

CoV

Mid

dle

East

Resp

irato

ry S

yndr

ome

coro

navi

rus,

SARS

-CoV

seve

re a

cute

resp

irato

ry sy

ndro

me

coro

navi

rus 2

, HC

oV-2

29E

hum

an c

oron

aviru

s 22

9E, H

CoV

-OC

43 h

uman

cor

onav

iruse

s sub

type

OC

43, R

NA ri

bonu

clei

c ac

id, I

V in

trave

nous

ly, N

A no

t ava

ilabl

e, P

O o

rally

, LPV

/r lo

pina

vir/r

itona

vir,

PgP

perm

eabi

lity

glyc

opro

tein

, Unc

lear

m

ultip

le p

ossi

ble

mec

hani

sms,

bid

twic

e da

ily, C

YP c

ytoc

hrom

e P4

50, W

T w

eigh

t, SC

subc

utan

eous

ly, I

FN in

terfe

ron,

HIV

hum

an im

mun

odefi

cien

cy v

irus

1203Drugs, PK/PD and DDI for SARS-CoV-2 Therapy

Tabl

e 2

PK

/PD

of a

ntiv

irals

and

oth

er d

rugs

use

d to

trea

t CO

VID

-19

Dru

gPD

met

ric (e

.g. I

C50

)Ty

pe o

f stu

dy u

sed

for

COV

ID-1

9 ex

peri-

men

ts

EC50

/EC

90 fo

r CO

VID

-19

(μM

)EC

50/E

C90

for o

ther

indi

catio

nsB

lood

con

cent

ratio

ns

Rem

desi

vir

EC50

In v

itro

(ver

o E6

cel

ls)

0.77

[53]

23.1

5 [5

4]0.

09 μ

M (M

ERS-

CoV

) in

a m

ice

mod

el

[55]

10 μ

M in

non

hum

an p

rimat

es w

as re

ache

d af

ter a

dos

e of

10 

mg/

kg IV

[56]

Not

e: tr

eatm

ent o

utco

mes

wer

e no

diff

eren

t fro

m c

ontro

l pat

ient

s hos

pita

lized

with

CO

VID

-19

[57]

EC90

In v

itro

(ver

o E6

cel

ls)

1.76

[53]

NA

Chl

oroq

uine

EC50

In v

itro

(ver

o E6

cel

ls)

1.13

–7.3

6[7

, 9, 5

3]0.

05 μ

M (P

lasm

odiu

m v

ivax

) in 

vitro

[58]

3.1 

μM (H

IV) i

n vi

tro [5

9]3.

0 μM

(MER

S-C

oV) i

n vi

tro [6

0]4.

1 μM

(SA

RS-

CoV

) in 

vitro

[60]

A c

once

ntra

tion

of 6

.9 μ

M is

ach

ieva

ble

in p

atie

nts a

fter a

500

 mg

dose

[53,

61

]; ho

wev

er, c

once

ntra

tions

as l

ow a

s 0.

5–1.

0 μM

wer

e al

so d

emon

strat

ed a

fter

a 30

0 m

g/12

 h re

gim

en (u

npub

lishe

d D

ata,

Bru

ggem

ann

on fi

le).

Not

e: h

ighe

r ad

vers

e eff

ects

and

leth

ality

wer

e fo

und

in p

atie

nts w

ith C

OV

ID-1

9 w

ho re

ceiv

ed

600 

mg/

12 h

for 1

0 da

ys c

ompa

red

with

45

0 m

g/12

 h o

n da

y 1

and

once

dai

ly

betw

een

days

2 a

nd 5

[10]

and

hig

her

mor

talit

y in

hos

pita

lized

pat

ient

s [10

, 11]

EC90

In v

itro

(ver

o E6

cel

ls)

6.9

[53]

0.35

8 μM

(P. v

ivax

) in 

vitro

at 3

0 h

[58]

Lopi

navi

r/rito

navi

rEC

50In

vitr

o (v

ero

E6 c

ells

)LP

V: 2

6.63

[54]

LPV:

8–1

1.6 

μM (M

ERS-

CoV

) in

mic

e/vi

tro [5

5, 6

0]LP

V: 1

7.1 

μM (S

AR

S-C

oV) i

n vi

tro [6

0]R

itona

vir:

24.9

 μM

(MER

S-C

oV) i

n a

mic

e m

odel

[55]

LPV

/r: 8

.5 μ

M (M

ERS-

CoV

) in

a m

ice

mod

el [5

5]

LPV

Cm

ax v

alue

s ave

rage

12.

72 μ

M (w

ith

p2.5

of 6

.36 

μM to

p97

.5 o

f 23.

85 μ

M)

and

riton

avir

Cm

ax v

alue

s ave

rage

0.

7 μM

(with

p2.

5 of

0.2

 μM

to p

97.5

of

2.22

 μM

) [62

]. N

ote:

trea

tmen

t out

com

es

wer

e no

diff

eren

t fro

m st

anda

rd o

f car

e in

hos

pita

lized

pat

ient

s with

CO

VID

-19

[37]

. LPV

/r co

mbi

ned

with

riba

rivin

and

in

terfe

ron-

β1β

dem

onstr

ated

bet

ter c

lini-

cal a

nd v

irolo

gica

l res

pons

e th

an L

PV/r

alon

e in

pat

ient

s with

mild

to m

oder

ate

dise

ase

[63]

Favi

pira

vir

IC50

In v

itro

(ver

o E6

cel

ls)

61.8

8 [5

3] >

100

[54]

67 μ

M fo

r Ebo

la [6

4]C

once

ntra

tions

of 1

190 ±

478 

μM w

ere

achi

eved

1 h

afte

r a fa

vipi

ravi

r 400

 mg

load

ing

dose

in n

onhu

man

prim

ates

[65]

. M

edia

n to

tal t

roug

h (p

redo

se) a

nd a

ver-

age

conc

entra

tions

of 3

60 a

nd 5

20 μ

M,

resp

ectiv

ely,

follo

win

g 12

00 m

g/12

 h

with

a lo

adin

g do

se o

f 600

0 m

g in

Eb

ola-

infe

cted

pat

ient

s [66

], w

ith a

fall

in

aver

age

conc

entra

tion

on d

ay 4

. Non

-lin

ear P

KN

ote:

faste

r vira

l cle

aran

ce a

nd ra

diol

ogi-

cal i

mpr

ovem

ent w

as re

porte

d in

pat

ient

s w

ho re

ceiv

ed fa

vipi

ravi

r whe

n co

mpa

red

with

LPV

/r [6

7]

1204 M. Zeitlinger et al.

PD p

harm

acod

ynam

ic, P

K p

harm

acok

inet

ic, I

C50

hal

f max

imal

inhi

bito

ry c

once

ntra

tion,

CO

VID

-19

coro

navi

rus

dise

ase

2019

, EC

50 h

alf m

axim

al e

ffect

ive

conc

entra

tion,

EC

90 9

0% e

ffect

ive

conc

entra

tion,

MER

S-C

oV M

iddl

e Ea

st Re

spira

tory

Syn

drom

e co

rona

viru

s, NA

not

ava

ilabl

e, H

IV h

uman

imm

unod

efici

ency

viru

s, SA

RS-C

oV s

ever

e ac

ute

resp

irato

ry s

yndr

ome

coro

navi

rus

1,

LPV/

r lop

inav

ir/rit

onav

ir, IF

N in

terfe

ron,

HC

V he

patit

is C

viru

s, SC

subc

utan

eous

ly, P

egIF

N p

egyl

ated

inte

rfero

n, IV

intra

veno

usly

, Cm

ax m

axim

um c

once

ntra

tion

Tabl

e 2

(con

tinue

d)

Dru

gPD

met

ric (e

.g. I

C50

)Ty

pe o

f stu

dy u

sed

for

COV

ID-1

9 ex

peri-

men

ts

EC50

/EC

90 fo

r CO

VID

-19

(μM

)EC

50/E

C90

for o

ther

indi

catio

nsB

lood

con

cent

ratio

ns

Rib

aviri

nEC

50In

vitr

o (v

ero

E6 c

ells

)10

9.50

[53]

> 10

0 [5

4]40

.94 ±

12.1

7 μM

(MER

S-C

oV) i

n vi

tro

[17]

Con

cent

ratio

n ra

nge

betw

een

25.0

and

10

.65 

μM a

chie

ved

with

a ri

bavi

rin d

ose

regi

men

of 4

00–6

00 m

g/12

 h [6

8]A

rbid

ol (U

mife

novi

r)EC

50In

vitr

o (v

ero

E6 c

ells

)4.

11 u

M (3

.55–

4.73

) [69

]24

.72 

μM (A

vian

infe

ctio

us b

ronc

hitis

vi

rus a

s rep

rese

ntat

ive

for C

oron

aviri

-da

e) [7

0]

Con

cent

ratio

ns o

f 1.4

7, 2

.60

and

4.53

 μM

ac

hiev

ed a

fter 0

.2, 0

.4 a

nd 0

.8 g

dos

es,

resp

ectiv

ely

[71]

Not

e: tr

eatm

ent o

utco

mes

wer

e re

porte

d to

be

no d

iffer

ent f

rom

stan

dard

of c

are

(sym

ptom

atic

and

supp

ortiv

e tre

atm

ent)

in h

ospi

taliz

ed p

atie

nts w

ith C

OV

ID-1

9 in

a re

trosp

ectiv

e co

hort

[72]

Hyd

roxy

chlo

roqu

ine

EC50

In v

itro

(ver

o E6

cel

ls)

0.72

 μM

[7] (

outly

ing

valu

e)4.

51–1

2.96

[9]

Con

cent

ratio

n > 1.

49 μ

M (>

500 

ng/m

l) ac

hiev

able

follo

win

g a

6 m

g/kg

/day

dos

-in

g re

gim

en [7

3]N

ote:

trea

tmen

t out

com

es w

ere

no d

iffer

ent

from

con

trol p

atie

nts h

ospi

taliz

ed w

ith

COV

ID-1

9 [1

2], a

nd o

bser

vatio

nal d

ata

show

incr

ease

d m

orta

lity

[11]

Con

cent

ratio

n sh

own

to re

duce

vi

ral t

iters

80 μ

M (Z

ika

viru

s) in

 vitr

o [7

4]

PegI

FN-α

2βEC

50N

AN

A0.

04 μ

g/L

(HC

V p

atie

nts)

[6]

Cm

ax o

f 0.5

3 μg

/L in

pat

ient

s afte

r 1.5

 μg/

kg S

C [7

5]IF

N-β

1βEC

50N

AN

A17

.64 ±

1.09

UI/m

l (M

ERS-

CoV

) [17

], 1.

37 U

/ml (

MER

S-C

oV) [

76]

Con

cent

ratio

n of

240

UI/m

l fol

low

ing

8 m

illio

n IU

 SC

[77]

IFN

-β1β

EC90

NA

NA

38.8

 U/m

l (M

ERS-

CoV

) [76

]C

amos

tat

EC50

In v

itro

(Cal

u-3

cells

)0.

087–

1 [7

8, 7

9]0.

198–

1 uM

(SA

RS-

CoV

) [78

, 79]

0.44

4 uM

(MER

S-C

oV) [

79]

Con

cent

ratio

n of

589

 uM

was

ach

ieve

d 12

 h a

fter C

amos

tat 4

0 m

g IV

adm

inist

ra-

tion

in h

uman

s [49

]EC

90In

vitr

o (C

alu-

3 ce

lls)

5 [7

8]5 

uM (S

AR

S-C

oV; M

ERS-

CoV

) [78

]N

afam

osta

tEC

50In

vitr

o (C

alu-

3 ce

lls)

0.00

5 [7

9]0.

0059

 uM

(MER

S-C

oV) [

79]

0.00

14 u

M (S

AR

S-C

oV) [

79]

Con

cent

ratio

ns o

f 41,

116

and

174

 uM

afte

r do

ses o

f 10,

20

and

40 IV

, res

pect

ivel

y [8

0]

1205Drugs, PK/PD and DDI for SARS-CoV-2 Therapy

Tabl

e 3

Dru

g–dr

ug in

tera

ctio

ns o

f pro

pose

d an

tivira

l com

bina

tions

aga

inst

coro

navi

rus

Prop

osed

com

bina

tion

(with

clin

ical

tri

al re

fere

nce

if av

aila

ble)

Phar

mac

odyn

amic

ratio

nale

Dru

g–dr

ug in

tera

ctio

ns w

ith le

vel

of se

verit

y an

d th

erap

eutic

adv

ice

[81]

Leve

l of e

vide

nce:

1.

Clin

ical

tria

l in

coro

navi

rus

2. R

etro

spec

tive

clin

ical

dat

a3.

In v

ivo

anim

al o

r in 

vitro

dat

a

Rib

aviri

n + L

PV/r

[82]

Inhi

bitio

n of

repl

icat

ion

PLU

S in

hibi

tion

of

RN

A sy

nthe

sis

Incr

ease

dris

k of

live

r tox

icity

Leve

l of s

ever

ity: m

ajor

Ther

apeu

tic a

dvic

e: m

onito

r for

in

crea

sed

liver

toxi

city

1. C

linic

al tr

ials

: No

data

2. R

etro

spec

tive

clin

ical

dat

a: (a

) Ret

rosp

ectiv

e m

atch

ed c

ohor

t stu

dy fo

r SA

RS-

CoV

infe

c-tio

n: 4

1 ca

ses t

reat

ed w

ith L

PV/r

+ ri

bavi

rin v

s. 11

1 hi

storic

al

cont

rols

trea

ted

with

riba

virin

alo

ne; b

ette

r clin

ical

out

com

e (A

RD

S an

d de

ath)

at d

ay 2

1 af

ter o

nset

of s

ympt

oms:

2.4

% v

s. 28

.8%

; p <

0.00

1. N

o di

ffere

nce

in o

utco

me

repo

rted

for e

arly

vs

. del

ayed

trea

tmen

t [15

](b

) Mul

ticen

ter r

etro

spec

tive

mat

ched

coh

ort s

tudy

for S

AR

S-C

oV in

fect

ion:

75

case

s tre

ated

with

LPV

/r +

riba

virin

vs.

977

cont

rols

trea

ted

with

riba

virin

. Red

uctio

n in

dea

th (2

.3%

vs.

15.6

%; p

< 0.

05) a

nd in

tuba

tion

(0%

vs.

11%

; p <

0.05

) was

ev

iden

t onl

y in

the

subg

roup

of i

nitia

l tre

atm

ent w

ith L

PV/r;

no

sign

ifica

nt d

iffer

ence

in th

e la

te tr

eatm

ent g

roup

[38]

(c) M

ERS-

CoV

infe

ctio

n: p

ost-e

xpos

ure

prop

hyla

xis w

ith

ribav

irin +

LPV

/r in

43

heal

thca

re w

orke

rs re

sulte

d in

a 4

0%

redu

ctio

n in

the

risk

of M

ERS-

CoV

infe

ctio

n, w

ith n

o se

vere

ad

vers

e ev

ents

dur

ing

treat

men

t [83

]3.

In v

ivo

anim

al o

r in 

vitro

dat

a:In

vitr

o ch

ecke

rboa

rd a

ssay

for s

yner

gy o

n SA

RS-

CoV

dem

on-

strat

ed in

hibi

tion

of th

e cy

topa

thic

effe

ct w

ith a

con

cent

ratio

n of

LPV

of 1

 μg/

ml w

ith ri

bavi

rin 6

.25 

μg/m

l whe

n th

e vi

ral

inoc

ulum

was

< 50

med

ian

tissu

e cu

lture

infe

ctio

us d

ose

[15,

84

]LP

V/r

+ A

rbid

ol [8

2]In

hibi

tion

of re

plic

atio

n PL

US

inhi

bitio

n of

R

NA

synt

hesi

s PLU

S in

hibi

tion

of v

iral e

ntry

No

clin

ical

dat

a av

aila

ble

CY

P3A

4 is

maj

or p

athw

ay o

f m

etab

olis

m fo

r arb

idol

; stro

ng

inhi

bitio

n of

CY

P3A

4-m

edia

ted

met

abol

ism

of a

rbid

ol b

y rit

ona-

vir i

s pla

usib

leLe

vel o

f sev

erity

: Unk

now

nTh

erap

eutic

adv

ice:

Mon

itor f

or

incr

ease

d to

xici

ty o

f arb

idol

[70]

1. C

linic

al tr

ials

: No

data

2. R

etro

spec

tive

clin

ical

dat

a: C

ase

serie

s (n =

4) o

f mild

or

seve

re C

OV

ID-1

9 pn

eum

onia

succ

essf

ully

trea

ted

with

LP

V/r

+ ar

bido

l + S

hufe

ng Ji

edo

Cap

sule

(tra

ditio

nal C

hine

se

med

icin

e) [8

5, 8

6]3.

In v

ivo

anim

al o

r in 

vitro

dat

a: N

o da

ta

1206 M. Zeitlinger et al.

Tabl

e 3

(con

tinue

d)

Prop

osed

com

bina

tion

(with

clin

ical

tri

al re

fere

nce

if av

aila

ble)

Phar

mac

odyn

amic

ratio

nale

Dru

g–dr

ug in

tera

ctio

ns w

ith le

vel

of se

verit

y an

d th

erap

eutic

adv

ice

[81]

Leve

l of e

vide

nce:

1.

Clin

ical

tria

l in

coro

navi

rus

2. R

etro

spec

tive

clin

ical

dat

a3.

In v

ivo

anim

al o

r in 

vitro

dat

a

Chl

oroq

uine

+ L

PV/r

Inhi

bitio

n of

repl

icat

ion

PLU

S in

hibi

tion

of v

iral

entry

Incr

ease

dris

k of

QTc

pro

long

atio

n (p

oten

-tia

lly d

ange

rous

inte

ract

ion)

Inhi

bitio

n of

CY

P3A

-med

iate

d m

etab

olis

m o

fch

loro

quin

e by

rito

navi

rLe

vel o

f sev

erity

: Maj

orTh

erap

eutic

adv

ice:

Mon

itor

ECG

and

mon

itor f

or in

crea

sed

toxi

city

of c

hlor

oqui

ne if

use

d in

co

mbi

natio

n. D

ose

redu

ctio

n of

ch

loro

quin

e m

ight

be

nece

ssar

y in

cas

e of

seve

re to

xici

ty

1. C

linic

al tr

ials

: No

data

, but

ong

oing

ope

n-la

bel s

tudy

cur

-re

ntly

bei

ng u

nder

take

n in

Chi

na (C

hiC

TR20

0002

9741

) [87

]2.

Ret

rosp

ectiv

e cl

inic

al d

ata:

No

data

3. In

 viv

o an

imal

or i

n vi

tro d

ata:

No

data

Emtri

cita

bine

+ te

nofo

vir (

Truv

ada)

Inhi

bitio

n of

RN

A sy

nthe

sis (

dual

ther

apy)

No

data

1. C

linic

al tr

ials

: No

data

2. R

etro

spec

tive

clin

ical

dat

a: N

o da

ta3.

In v

ivo

anim

al o

r in 

vitro

dat

a: N

o da

taFa

vipi

ravi

r + in

terfe

ron

Inhi

bitio

n R

NA

synt

hesi

s PLU

S im

mun

e m

odu-

latio

nN

o da

ta1.

Clin

ical

tria

ls: O

pen-

labe

l, no

nran

dom

ized

, com

para

tive

cont

rolle

d stu

dy in

80

patie

nts w

ith S

AR

S-C

oV-2

infe

ctio

n.

Thirt

y-fiv

e pa

tient

s wer

e tre

ated

with

FPV

plu

s inh

aled

IFN

-α.

For

ty-fi

ve h

istor

ic c

ontro

ls re

ceiv

ed L

PV/r

plus

inha

led

IFN

-α. T

reat

men

t with

FPV

/IFN

led

to sh

orte

r vira

l cle

aran

ce

time

and

impr

ovem

ent i

n ch

est i

mag

ing

at D

14. F

ewer

adv

erse

ev

ents

wer

e fo

und

in th

e FP

V/IF

N a

rm [6

7]2.

Ret

rosp

ectiv

e cl

inic

al d

ata:

No

data

3. In

 viv

o an

imal

or i

n vi

tro d

ata:

No

data

Emtri

cita

bine

+ te

nofo

vir (

Truv

ada)

+

LPV

/r [8

8]In

hibi

tion

of re

plic

atio

n PL

US

inhi

bitio

n of

R

NA

synt

hesi

sIn

crea

sed

teno

fovi

r abs

orpt

ion

(i.e.

32%

AU

C

incr

ease

; 51%

Cm

in in

crea

se)

thro

ugh

P-gl

ycop

rote

inin

hibi

tion

Leve

l of s

ever

ity: M

oder

ate

Ther

apeu

tic a

dvic

e: M

onito

r for

teno

fovi

r-ass

ocia

ted

toxi

city

1. C

linic

al tr

ials

: No

data

2. R

etro

spec

tive

clin

ical

dat

a: N

o da

ta3.

In v

ivo

anim

al o

r in 

vitro

dat

a: N

o da

ta

1207Drugs, PK/PD and DDI for SARS-CoV-2 Therapy

Tabl

e 3

(con

tinue

d)

Prop

osed

com

bina

tion

(with

clin

ical

tri

al re

fere

nce

if av

aila

ble)

Phar

mac

odyn

amic

ratio

nale

Dru

g–dr

ug in

tera

ctio

ns w

ith le

vel

of se

verit

y an

d th

erap

eutic

adv

ice

[81]

Leve

l of e

vide

nce:

1.

Clin

ical

tria

l in

coro

navi

rus

2. R

etro

spec

tive

clin

ical

dat

a3.

In v

ivo

anim

al o

r in 

vitro

dat

a

Inte

rfero

n + ri

bavi

rinIm

mun

e m

odul

atio

n PL

US

inhi

bitio

n of

RN

A

synt

hesi

sN

o da

ta1.

Clin

ical

tria

ls: O

ngoi

ng o

pen-

labe

l, si

ngle

-cen

ter,

pros

pec-

tive,

rand

omiz

ed c

ontro

lled

clin

ical

tria

l in

Chi

na c

ompa

ring

LPV

/r pl

us IF

N-α

vs.

ribav

irin

plus

IFN

-α, v

s. LP

V/r

plus

IF

N-α

plu

s rib

aviri

n [8

9]2.

Ret

rosp

ectiv

e cl

inic

al d

ata:

(a) M

ultic

ente

r obs

erva

tiona

l stu

dy in

crit

ical

ly il

l pat

ient

s with

M

ERS-

CoV

infe

ctio

n. O

f 349

MER

S-C

oV-in

fect

ed p

atie

nts,

144

rece

ived

RBV

/rIFN

(rIF

N-α

2a, r

IFN

-α2b

or r

IFN

-ß1a

). Tr

eatm

ent w

as n

ot a

ssoc

iate

d w

ith a

redu

ctio

n in

90-

day

mor

-ta

lity

or fa

ster M

ERS-

CoV

RN

A c

lear

ance

[90]

b. R

etro

spec

tive

coho

rt stu

dy o

f pat

ient

s with

MER

S-C

oV

requ

iring

ven

tilat

ion

supp

ort w

ho re

ceiv

ed su

ppor

tive

care

(n

= 24

) vs.

oral

riba

virin

+ pe

gyla

ted

IFN

-α2a

(n =

20).

Trea

t-m

ent w

ith ri

bavi

rin +

IFN

-α2a

was

ass

ocia

ted

with

sign

ifi-

cant

ly im

prov

ed su

rviv

al a

t 14 

days

, but

not

at 2

8 da

ys [9

1]3.

In v

ivo

anim

al o

r in 

vitro

dat

a: S

yner

gisti

c an

tivira

l effe

ct

betw

een

ribav

irin

and

type

I IF

N (i

.e. I

FN-α

[84,

92]

or I

FN-ß

[8

4, 9

2, 9

3]) o

n SA

RS-

CoV

was

des

crib

ed in

two

studi

es

perfo

rmed

in h

uman

and

Ver

o ce

ll lin

esLP

V/r

+ in

terfe

ron +

riba

virin

Imm

une

mod

ulat

ion

PLU

S in

hibi

tion

of R

NA

sy

nthe

sis P

LUS

inhi

bitio

n of

repl

icat

ion

Leve

l of s

ever

ity: M

ajor

Ther

apeu

tic a

dvic

e: M

onito

r for

in

crea

sed

risk

for h

epat

otox

ic-

ity (f

or c

ombi

natio

n pr

otea

se

inhi

bito

r + ri

bavi

rin a

nd p

rote

ase

inhi

bito

r + in

terfe

ron)

1. C

linic

al tr

ials

: One

ope

n-la

bel,

rand

omiz

ed, m

ultic

ente

r, ph

ase

II tr

ial i

n H

ong

Kon

g in

127

pat

ient

s with

con

-fir

med

SA

RS-

CoV

2 in

fect

ion.

Eig

hty-

six

patie

nts r

ecei

ved

LPV

/r +

inte

rfero

n-β1

b + ri

bavi

rin c

ombi

natio

n tre

atm

ent,

and

41 re

ceiv

ed L

PV/r

alon

e. T

he c

ombi

natio

n gr

oup

had

a si

gnifi

cant

ly sh

orte

r med

ian

time

from

star

t of s

tudy

trea

tmen

t to

neg

ativ

e na

soph

aryn

geal

swab

, and

shor

ter d

urat

ion

of

hosp

italiz

atio

n th

an th

e co

ntro

l gro

up [6

3]O

ngoi

ng o

pen-

labe

l, si

ngle

-cen

ter,

pros

pect

ive,

rand

omiz

ed

cont

rolle

d cl

inic

al tr

ial i

n C

hina

com

parin

g LP

V/r

plus

IFN

-α

vs. r

ibav

irin

plus

IFN

-α, v

s. LP

V/r

plus

IFN

-α p

lus r

ibav

irin

[89]

2. R

etro

spec

tive

clin

ical

dat

a: T

wo

case

repo

rts, o

ne p

atie

nt

reco

vere

d, o

ne p

atie

nt d

ied

durin

g ho

spita

l sta

y du

e to

sept

ic

shoc

k [9

4, 9

5]3.

In v

ivo

anim

al o

r in 

vitro

dat

a: N

o da

ta

1208 M. Zeitlinger et al.

Tabl

e 3

(con

tinue

d)

Prop

osed

com

bina

tion

(with

clin

ical

tri

al re

fere

nce

if av

aila

ble)

Phar

mac

odyn

amic

ratio

nale

Dru

g–dr

ug in

tera

ctio

ns w

ith le

vel

of se

verit

y an

d th

erap

eutic

adv

ice

[81]

Leve

l of e

vide

nce:

1.

Clin

ical

tria

l in

coro

navi

rus

2. R

etro

spec

tive

clin

ical

dat

a3.

In v

ivo

anim

al o

r in 

vitro

dat

a

Hyd

roxy

chlo

roqu

ine +

azith

rom

ycin

Imm

une

mod

ulat

ion

PLU

S in

hibi

tion

of v

iral

entry

Incr

ease

dris

k of

QTc

pro

long

atio

n (p

oten

-tia

lly d

ange

rous

inte

ract

ion)

Leve

l of s

ever

ity: M

ajor

Ther

apeu

tic a

dvic

e: M

onito

r EC

G

1. C

linic

al tr

ials

: One

ope

n-la

bel,

non-

rand

omiz

ed c

linic

al st

udy

in 3

6 pa

tient

s with

con

firm

ed S

AR

S-C

oV2

infe

ctio

n (in

terim

an

alys

is o

f ong

oing

tria

l) [9

6]. O

f 36

patie

nts,

14 re

ceiv

ed

hydr

oxyc

hlor

oqui

ne tr

eatm

ent,

6 re

ceiv

ed h

ydro

xych

loro

quin

e/az

ithro

myc

in c

ombi

natio

n tre

atm

ent a

nd 1

6 w

ere

cont

rols

. Th

e pr

opor

tion

of p

atie

nts w

ith n

egat

ive

PCR

in n

asop

hary

n-ge

al sa

mpl

es w

as si

gnifi

cant

ly h

ighe

r in

hydr

oxyc

hlor

o-qu

ine-

treat

ed p

atie

nts a

t day

s 3–6

pos

t-inc

lusi

on v

s. co

ntro

l pa

tient

s. If

hyd

roxy

chlo

roqu

ine

was

use

d in

com

bina

tion

with

az

ithro

myc

in, t

he p

ropo

rtion

of p

atie

nts w

ith n

egat

ive

PCR

in

naso

phar

ynge

al sa

mpl

es w

as si

gnifi

cant

ly h

ighe

r on

days

3–6

w

hen

com

pare

d w

ith p

atie

nts t

reat

ed w

ith h

ydro

xych

loro

quin

e m

onot

hera

py. O

ne o

pen-

labe

l, no

n-ra

ndom

ized

clin

ical

stud

y in

80

patie

nts w

ith c

onfir

med

SA

RS-

CoV

2 in

fect

ion

[97]

. Of

80 p

atie

nts,

all e

xpec

t 2 im

prov

ed c

linic

ally

. A ra

pid

fall

in

naso

phar

ynge

al v

iral l

oad

was

obs

erve

d, w

ith 8

3% n

egat

ive

at

day

7, a

nd 9

3% a

t day

82.

Ret

rosp

ectiv

e cl

inic

al d

ata:

One

retro

spec

tive

coho

rt stu

dy o

f 14

38 p

atie

nts h

ospi

taliz

ed fo

r CO

VID

-19

in 2

5 ho

spita

ls in

m

etro

polit

an N

ew Y

ork.

735

pat

ient

s rec

eive

d hy

drox

ychl

o-ro

quin

e + az

ithro

myc

in, 2

11 re

ceiv

ed a

zith

rom

ycin

alo

ne, 2

71

rece

ived

hyd

roxy

chlo

roqu

ine

alon

e, a

nd 2

21 re

ceiv

ed n

eith

er

drug

[98]

Ther

e w

e no

diff

eren

ces i

n ho

spita

l mor

talit

y be

twee

n di

ffere

nt

treat

men

tsO

ne re

trosp

ectiv

e stu

dy o

f 106

1 co

nfirm

ed S

AR

S-C

oV2

patie

nts

treat

ed w

ith h

ydro

xych

loro

quin

e + az

ithro

myc

in fo

r at l

east

3 da

ys in

Mar

seill

e, F

ranc

e. G

ood

clin

ical

and

viro

logi

cal c

ure

was

obt

aine

d in

973

(91.

7%) p

atie

nts w

ithin

10 

days

[99]

Retro

spec

tive

elec

troni

c ca

se re

cord

revi

ew o

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1209Drugs, PK/PD and DDI for SARS-CoV-2 Therapy

3.4 Most Commonly Used Supportive Agents (Intensive Care Unit, Pain, Fever, Anticoagulation)

Supportive care with other pharmacological agents, includ-ing antibiotics, sedatives, analgesics, and anticoagulants, need to be considered when treating with antiviral and other repurposed agents, particularly in the critical care setting. Electronic supplementary Table 1 lists the major drugs by class and highlights potential interactions. In particular, cau-tion should be exercised for CYP3A4 DDIs with narrow therapeutic index drugs, such as anticoagulants (warfarin, acenokumarol, dabigatran, rivaroxaban, and apixaban) and immunosuppressant agents in transplant recipients in whom additional monitoring may be required. For patients sedated with midazolam, dose reduction should be considered when patients are treated with CYP3A4 inhibitors, such as LPV/r, as there is a significant risk of oversedation, resulting in unnecessary prolongation of intensive care unit (ICU) stay [20]. There are multiple potential interactions resulting in cardiac complications, including prolonged QT interval with (hydroxy)chloroquine combinations and LPV/r, that neces-sitate monitoring. As these DDI are substantial, the balance of risk versus benefit should be carefully considered prior to drug administration to prevent significant morbidities.

According to a preliminary report in patients hospital-ized with COVID-19, dexamethasone significantly reduced 28-day mortality among those patients receiving invasive mechanical ventilation or oxygen at randomization, but not among patients not receiving respiratory support [21]. If these data hold true, at the moment corticosteroids belong to the most active intervention in patients with severe COVID-19 disease. In this aspect, it should also be noted that while dexamethasone is a potent inductor of CYP3A4 induction, this effect seems to be less relevant for the common alterna-tive, betamethasone [22].

3.5 Interaction Between Antivirals and Supportive Drugs

The potential interactions for most drugs used to treat COVID-19, and comedications, are provided in detail in electronic supplementary Table 2. It is emphasized that not all described interactions are necessarily clinically relevant, and the ultimate decision on the need for avoiding a certain combination or dose adjustment must be taken by the treat-ing physician.

DDIs are an important consideration for all therapies used to treat COVID-19. This is especially the case with repurposed antiretroviral drugs and (hydroxy)chloroquine, which have many potential DDIs. Clinicians treating patients infected with SARS-CoV-2 need to carefully consider the potential for DDIs before commencing therapy. Many DDIs

may be mitigated by simple measures such as continuous electrocardiogram (ECG) monitoring or by having maxi-mum allowable QT intervals (e.g. 450 ms) for the interact-ing combinations to be used. The ritonavir component of LPV/r is deliberately used to inhibit CYP3A4 and thereby increase antiretroviral drug concentrations; however, this leads to a significant potential to increase concentrations of other coadministered therapies that are CYP3A4 substrates. Notably, the interaction between (hydroxy)chloroquine and other agents that may inhibit drug CL can result in cardiac toxicity and patients should be monitored closely. Based on the long half-life of (hydroxy)chloroquine (in the magnitude of several weeks), interactions might persist for several days after treatment has ceased. This may be especially problem-atic in critically ill patients with pre-existing cardiovascular morbidity, and extreme caution should be observed. The use of triazole antifungals should be avoided or carefully monitored if administered concurrently with LPV/r due to DDIs. Potential DDIs are reported between either LPV/r and important drugs commonly used in the critical care setting, including ketamine, rocuronium, and many of the opioid agents. Utmost care is required when considering the coadministration of these agents with antiretroviral drugs in critically ill patients. The newer investigational antiviral agents, remdesivir and favipiravir, appear to have a lower potential for DDIs; however, the main concern with their use is decreased concentrations if coadministered with enzyme inducers. (Hydroxy)chloroquine may prolong the QT inter-val, therefore ECG monitoring is required when they are coadministered with other agents known to cause QT inter-val prolongation. Coadministration of (hydroxy)chloroquine with drugs that are known to prolong the QT interval, such as amiodarone and flecanide, is not recommended. However, clinical experience with these drugs is much less than the repurposed antiretrovirals. A comprehensive and evolving DDI database has been created by the University of Liv-erpool and this should be consulted for potential DDIs not covered in our review [3].

3.6 The Effect of Extracorporeal Treatments on the PK of COVID‑19 Therapies

Systemic inflammatory response syndrome (SIRS) may occur with the use of extracorporeal treatments, and may cause alterations in CYP‐mediated metabolism. SIRS increases activity of all CYPs, except CYP3A4, which decreases. In children, CYP enzymes are commonly imma-ture in neonates and take time to reach similar activity lev-els as adults [23]. In this section, as well as in Table 4, we summarize the principles of PK alterations that occur with extracorporeal membrane oxygenation (ECMO) and renal replacement therapy (RRT) to impact drug exposure and thereby dose. Although limited studies have been conducted

1210 M. Zeitlinger et al.

on COVID-19 therapies, optimized dosing should consider these potential impacts on individual patients.

3.7 The Impact of Extracorporeal Membrane Oxygenation

The most common mechanisms by which ECMO is likely to affect the PK of drugs are sequestration by the oxygenator and tubing in the ECMO circuit, leading to reduced circu-lating drug concentrations [23]. While lipophilic drugs and highly protein-bound drugs are more likely to be seques-tered in the circuit, hydrophilic drugs can be significantly affected by hemodilution and changes in albumin concen-tration, potentially leading to altered protein binding and an increased Vd. Indeed, an increased free fraction means more distribution from the central compartment into the peripheral compartments (i.e. tissues), leading to an increased apparent Vd [24]

3.8 The Impact of Renal Replacement Therapy

Sepsis-related acute kidney injury often develops in the con-text of multiple organ dysfunction syndrome and leads to relevant modifications of several PK parameters. Moreover, high volumes of fluid resuscitation, commonly required in critically ill patients [25], may significantly affect the Vd of several drugs [26]. When Vd of a drug is typically small since the drug is mostly retained in the intravascular com-partment (where protein binding is high), clinically signif-icant removal of small drugs by RRT is unlikely. Where Vd is < 1.0 L/kg and protein binding is not high (> 80%), the commencement of RRT adds further complexities for

dosing, with possible extracorporeal CL. Renally excreted drugs are usually affected by RRT to a much greater extent than hepatically excreted drugs [27]. Only the free (i.e. unbound) drug is cleared across the RRT filter. With the exception of a few drugs, the molecular weight (MW) of the most commonly used antimicrobial agents is lower than 1000 Da and plays a key role, especially in diffusive RRT modalities, as the sieving coefficient (SC) of a molecule is inversely proportional to MW. The SC is generally similar for drugs with a MW around 1000–1500 Da in convective modalities. However, in diffusive techniques, the ratio of dialysate to plasma solute concentration (saturation coef-ficient [SA]) is more strictly dependent on MW and tends to decrease progressively as MW increases [28]. Whereas intermittent hemodialysis (IHD) or continuous venovenous hemodialysis (CVVHD) are essentially diffusive techniques, continuous venovenous hemofiltration (CVVH) is a convec-tive technique, and continuous venovenous hemodiafiltration (CVVHDF) is a combination of both. As a general rule, the efficiency of drug removal by the different techniques is expected to be CVVHDF > CVVH > CVVHD/IHD, but this can still vary greatly depending on the physicochemical properties of each drug and the CRRT settings [29]. Dialyzer membrane characteristics (cut-off) may also play a key role.

3.9 PK Data of Drugs Active Against SARS‑CoV‑2

Table 4 extrapolates basic drug physicochemistry and known PK data to predict the likely effects of ECMO on PK. Sparse data on the IHD CL of (hydroxy)chloroquine are available and suggest that the high Vd of (hydroxy)chloroquine limits significant alteration in drug concentrations [30]. As such, ECMO is predicted to have minimal impact on the drug

Table 4 Expected PK of the antivirals used to treat COVID-19 with extracorporeal support treatments

RRT renal replacement therapies, ECMO extracorporeal membrane oxygenation, NA not available, Vd volume of distribution, IFN interferona For example, systemic inflammatory response syndrome (SIRS) caused by extracorporeal life support systemb Sequestration of drug to the ECMO oxygenator is likely, but is unlikely to affect dosing needs

Name of antiviral Effects on pharmacokinetic parameters Protein binding (%)

RRT ECMO Extracorporeal systemic inflammatory responsea

Remdesivir NA NA NA NAChloroquine – Likelyb Alterations in cytochrome metabolism 40–60 [25, 31]Lopinavir – Likelyb Alterations in cytochrome metabolism 98–99 [101]Ritonavir – Likelyb Alterations in cytochrome metabolism 99 [102]Favipiravir – Increases Vd Alterations in cytochrome metabolism 54 [32]Ribavirin – Increases Vd – 0 [26]Arbidol (Umifenovir) – – Alterations in cytochrome metabolism NAHydroxychloroquine – Likelyb Alterations in cytochrome metabolism 40–60 [25, 31]PegIFN-α2β – – – NAIFN-α1β – – – NAIFN-α – – – NA

1211Drugs, PK/PD and DDI for SARS-CoV-2 Therapy

concentrations of (hydroxy)chloroquine, although seques-tration onto the oxygenator and circuit tubing cannot be excluded. There is also the hypothesis that (hydroxy)chlo-roquine rapidly partitions intracellularly, potentially result-ing in minor effects overall and in the vascular compartment [25]. The PK of LPV/r in hemodialysis suggests that dosing adjustments are unnecessary in treatment-naive patients, in part due to the high protein binding of these drugs [31]. CVVH has no clinically relevant contribution to total CL of favipiravir [32]. For ribavirin, CL was reduced by 50% via IHD [33], which is not considered significant enough to justify increasing the dose based on increases in dialysate or RRT filtration flow rate [34]. No significant effect of RRT on IFN concentrations is predicted due to the MW of the IFN compounds which usually exceeds 15 kDa [35, 36].

4 Discussion

We have provided an in-depth rapid review on the preclinical and clinical antiviral treatment options for SARS-CoV-2. It should be emphasized that although the approach in the cur-rent review is pragmatic to allow for real-time assessment of international practice, it cannot guarantee that all experimen-tal combinations have been captured. However, the thera-peutic investigations for COVID-19 are highly dynamic and almost daily new treatment options are empirically tested in clinical practice globally. More importantly, the quality of data regarding the safe and effective use of treatment options are generally poor and strong recommendations cannot be provided regarding the superiority of one treatment or com-bination over another. It is clear with absolute certainty that robust controlled clinical trials are imperative. Such studies must use either clinical endpoints (demonstrating a benefit in how the patient feels, functions, or survives) or improv-ing meaningful biomarker performance such as time of viral shedding. Regarding the study design, randomization, blind-ing, and an appropriate control (either a comparator that has been proven effective or placebo) are recommended. Meanwhile, all antiviral therapies should be used with cau-tion due to the significant drug interactions, risk for adverse events, and the need to evaluate optimal doses for treating mild versus serious infections.

All drugs presented in Table 1 should be seen as possible treatment options for patients with, or very likely to develop, a critical COVID-19 disease despite no strong recommenda-tions being available. We found that PK/PD indices indicate that many of the currently used treatment regimens fail to achieve sufficient concentrations when EC50 values are com-pared with plasma PK, which might partially explain limited clinical success of these combinations. Before investigation of any new combination empirically, PK/PD models with Monte Carlo simulations should be used to predict success

and, wherever possible, integrate an adaptive design to also account for tolerability. Failure to develop these models might lead to suboptimal drug exposure in patients, resulting in erroneous omission of therapeutic options before explor-ing their full potential.

Relevant DDIs exist both between combinations of anti-virals and between antivirals and supportive therapies. Since many of the combinations have not been widely used in the ICU, healthcare providers should be alerted to closely moni-tor for DDIs. With the omnipresent work overload related to the COVID-19 crisis within hospitals and ICUs, applications (apps) or programs should be developed to support real-time clinical decisions and dose adaption.

A recent study of LPV/r showed no effect against SARS-CoV-2 [37] but this conclusion should be interpreted with caution. Only 199 patients were randomized and the non-significant trend showed a 5.8% decrease in mortality with LPV/r versus no treatment. If this is the true effect size, a larger sample size is required. Furthermore, the high overall mortality reported in this study suggests that these patients had severe disease, and the late initiation of therapy (i.e. within 12 days after the onset of symptoms) may have affected the results. As such, the clinical benefit of early initiation of LPV/r monotherapy should be further investi-gated. The clinical trials of SARS or MERS evaluated LPV/r in combination with ribavirin, rather than as monotherapy. Lopinavir and ribavirin have been found to be synergis-tic in vitro against SARS [15], and, more importantly, the combination of LPV/r and ribavirin reduced mortality and viral shedding when compared with historical controls [15]. Another study in SARS reported that early initiation of com-bination therapy consisting of LPV/r plus ribavirin, com-pared with historical controls treated with ribavirin alone, significantly reduced mortality and the need for ventilation; notably, there was no effect with delayed or late therapy [38]. Extrapolating these data to SARS-CoV-2 should be taken with caution since LPV and the protease inhibitor nelfinavir appears to exhibit good activity against SARS [16] but is less effective against MERS [17]. Nonetheless, LPV/r, ribavirin and IFN combinations should be investigated for in vitro synergy against SARS-CoV-2, and considered for clinical evaluation if the results are promising. One open-label RCT comparing LPV/r plus inhaled IFN-β plus ribavirin against LPV/r in SARS-CoV-2-positive patients reported a signifi-cantly shorter time from start of treatment to negative naso-pharyngeal swab, and shorter duration of hospitalization, when compared with the control group. Of note, we advise against the use of combinations of hydroxychloroquine with azithromycin due to emerging safety issues with this drug combination, in particular increased risk for QTc prolonga-tion [18].

In summary, there are promising therapeutic options for COVID-19 in the absence of a vaccine at present. The

1212 M. Zeitlinger et al.

encouraging RCT results for remdesivir provide some direc-tion for the treatment of COVID-19 patients and has led to positive evaluation of the drug for severe forms of COVID-19 by the European Medicines Agency and the FDA. Further to this, it is highly likely that one or more other agents men-tioned in this review, or, more plausibly, a combination, may emerge as a prophylactic or early treatment option with the potential to decrease viral shedding and transmission and/or reduce disease progression to the requirement of ventila-tory support.

From a PK/PD perspective, the development should not only focus on the discovery of new treatment options but should also investigate common key aspects of treatment, particularly the following.

• When is the optimal time point to start antiviral therapy, what is the required duration, and when is it too late to initiate treatment?

• In line with the open questions regarding dexametha-sone, when is it time to start anti-inflammatory drugs and which biomarkers can we use to tailor this therapy?

• What role can the individualization of therapy based on dose adaption and therapeutic drug monitoring (TDM) play in the treatment of COVID-19?

Meanwhile, due to the lack of highly effective and suf-ficiently evaluated treatment options, the most important strategy currently is avoidance of infection by the imple-mentation of optimal public health measures that incorpo-rate appropriate handwashing and social distancing. Fur-thermore, the use of rapid diagnostic tests to identify silent carriers, along with active disease, and the availability of personal protective equipment to protect from transmission, are critical to limit the massive spread of infection. Lastly, the development of vaccines (in which a clinical trial has been initiated in the US) is vital to immediately protect indi-vidual immunity and our global community long-term.

Acknowledgements Open access funding provided by Medical Uni-versity of Vienna. This review was performed by members of the PK/PD of Anti-Infectives Study Group (EPASG) of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID). JFS was funded by a United Kingdom Medical Research Council Fellowship (MR/M008665/1). JAR would like to acknowledge funding from the Australian National Health and Medical Research Council for a Centre of Research Excellence (APP1099452) and a Practitioner Fellowship (APP1117065).

Funding No funding was received for this manuscript.

Compliance with Ethical Standards

Conflict of interest Markus Zeitlinger, Birgit C.P. Koch, Roger J.M. Bruggemann, Pieter de Cock, Timothy Felton, Maya Christina Hites, Jennifer Le, Sonia Luque, Alasdair Peter Macgowan, Deborah J.E.

Marriott, Anouk E. Muller, Kristina Nadrah, David L. Paterson, Jo-seph F. Standing, João Paulo Marochi Telles, Michael Christoph Wöl-fl-Duchek, Michael Thy and Jason Roberts declare they have no con-flicts of interest associated with the content of the current manuscript.

Open Access This article is licensed under a Creative Commons Attri-bution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Com-mons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regula-tion or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by-nc/4.0/.

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Affiliations

Markus Zeitlinger1  · Birgit C. P. Koch2 · Roger Bruggemann3 · Pieter De Cock4 · Timothy Felton5,6 · Maya Hites7 · Jennifer Le8 · Sonia Luque9,10 · Alasdair P. MacGowan11 · Deborah J. E. Marriott12,13 · Anouk E. Muller14 · Kristina Nadrah15,16 · David L. Paterson17,18 · Joseph F. Standing19,20 · João P. Telles21 · Michael Wölfl‑Duchek22 · Michael Thy23,24 · Jason A. Roberts25,26,27,28,29 · the PK/PD of Anti‑Infectives Study Group (EPASG) of the European Society of Clinical Microbiology, Infectious Diseases (ESCMID)

1 Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria

2 Hospital Pharmacy, Erasmus MC, Rotterdam, The Netherlands

3 Radboud University Medical Center, Nijmegen, The Netherlands

4 Department of Pharmacy 2, Heymans Institute of Pharmacology, Ghent University Hospital, Ghent University, Ghent, Belgium

5 Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK

6 Intensive Care Unit, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, UK

7 Clinic of Infectious Diseases, CUB-Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium

8 Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, San Diego, CA, USA

9 Pharmacy Department, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain

10 Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital del Mar D’Investigacions Mèdiques (IMIM), Barcelona, Spain

11 Bristol Centre for Antimicrobial Research and Evaluation, Infection Sciences, Severn Pathology Partnership, North Bristol NHS Trust, Southmead Hospital, Westbury-On-Trym, Bristol, UK

12 St. Vincent’s Hospital, Darlinghurst, NSW, Australia13 University of New South Wales, Sydney, NSW, Australia

1216 M. Zeitlinger et al.

14 HaaglandenMC, The Hague and ErasmusMC, Rotterdam, The Netherlands

15 Department of Infectious Diseases, University Medical Centre Ljubljana, Ljubljana, Slovenia

16 Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia

17 University of Queensland Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia

18 Department of Infectious Diseases, Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia

19 Infection, Inflammation and Immunity, Great Ormond Street Institute of Child Health, University College London, London, UK

20 Department of Pharmacy, Great Ormond Street Hospital for Children, London, UK

21 Department of Infectious Diseases, AC Camargo Cancer Center, São Paulo, SP, Brazil

22 Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria

23 Infectious Diseases Department and Intensive Care Unit, Hospital Bichat, Paris, France

24 EA7323, Evaluation of Perinatal and Paediatric Therapeutics and Pharmacology, University Paris Descartes, Paris, France

25 University of Queensland Centre for Clinical Research, Faculty of Medicine and Centre for Translational Anti-Infective Pharmacodynamics, School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia

26 Department of Pharmacy, Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia

27 Department of Intensive Care Medicine, Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia

28 Division of Anaesthesiology Critical Care Emergency and Pain Medicine, Nîmes University Hospital, University of Montpellier, Nîmes, France

29 The University of Queensland Centre for Clinical Research, The University of Queensland, Royal Brisbane and Women’s Hospital, Butterfield St, Herston, QLD 4029, Australia